Hyaluronic acid is a type of muco-polysaccharide which is present at high level in the dermis and which maintains moisture and elasticity of the skin. The half-life of hyaluronic acid is as short as about one day, and hyaluronic acid level is known to decrease with aging. Thus, hitherto, hyaluronic acid and substances which can suppress decomposition of hyaluronic acid have been employed as, for example, cosmetics for the moisturizing or anti-aging purpose.
For example, some plant extracts, histamine H1-antagonist (Patent Document 1), and heparin (Patent Document 2) are known to have a hyaluronic acid decomposition-suppressing effect, and application of these substances to cosmetics and pharmaceuticals is now studied. Meanwhile, a chondroitin sulfate C derivative (Patent Document 3) and carnitine derivatives (Patent Document 4) are known to have a hyaluronic acid decomposition promoting effect.
In the beauty and medical fields, local injection of hyaluronic acid is widely known to provide a wrinkle-ameliorating effect. However, since the injected hyaluronic acid is decomposed and metabolized by an enzyme present in the body, the effect thereof cannot last for a long period, which is problematic.
In the pharmaceutical field, an intra-articular injection of high-molecule hyaluronic acid is used for the treatment of deformans arthritis or rheumatoid arthritis. However, due to a poor long-lasting effect, patients must periodically receive the injection. Thus, if decomposition of hyaluronic acid in the body can be controlled, the aforementioned poor long-lasting effect can be solved, whereby patient's compliance would be improved.
Hyaluronic acid is a polymer having a repeated structure formed of D-glucuronic acid and N-acetyl-D-glucosamine, and the molecular weight thereof ranges from the order of 1,000 to the order of 1,000,000. The physiological activity of hyaluronic acid is known to vary depending on its molecular weight. For example, a low-molecule hyaluronic acid having a molecular weight of 1,600 to 10,000 is known to exhibit angiogenesis action, while hyaluronic acid having a molecular weight of about 500,000 or less is known to induce various inflammation-related factors.
In diseases such as cancer, deformans arthritis (OA), and rheumatoid arthritis (RA), the synthesis/decomposition balance of hyaluronic acid is known to be lost. In bladder cancer, a large amount of low-molecule hyaluronic acid is detected in urine and bladder tissue. The malignancy of the cancer is correlated to the molecular weight of hyaluronic acid in the relevant tissue. In the case of high-malignancy cancer, both hyaluronic acid having a high molecular weight (about 2,000,000) and hyaluronic acid having a low molecular weight (about 10,000) are present. According to one report, low-molecule hyaluronic acid induces genesis of feeding vessels to the tumor tissue. The level and molecular weight of hyaluronic acid are known to decrease in the joint fluid of deformans arthritis patients and rheumatoid arthritis patients. Therefore, if the molecular weight of hyaluronic acid can be controlled, the desired effect of hyaluronic acid depending on the molecular weight can be attained, possibly leading to more effective therapy.
Meanwhile, there has been proposed a model of decomposition/metabolism of hyaluronic acid in the body which involves hyaluronidase (HYAL)1, HYAL2, and CD44 (HA receptor). According to the model, hyaluronic acid is decomposed outside the cells by the cooperative action of HYAL2 and CD44, to thereby form a 20 kDa fragment, or is incorporated into the endosome/lysosome path by the mediation of CD44, and decomposed by HYAL1 in lysosome to tetrasaccharide.
At present, six human hyaluronidase-related genes (HYAL1 to HYAL4, SPAM1, and HYALP1) are known. Proteins encoded by HYAL4, SPAM1, and HYALP1 are produced mainly in the testicles, while proteins encoded by HYAL1, HYAL2, and HYAL3 are present widely in the body. At present, the hyaluronic acid decomposition action of HYAL3 has not been clearly elucidated, and therefore, the aforementioned HYAL1 and HYAL2 are thought to have a high possibility of playing a main role in decomposition of hyaluronic acid. However, the mechanism of decomposition of hyaluronic acid cannot be completely elucidated only from the known hyaluronidase-related genes, and the actual mechanism is currently unknown.
The KIAA1199 gene of the present invention is a function-unknown expressed sequence tag (EST), and the KIAA1199 gene was suggested to have a relationship with cancer or hearing impairment. For example, the KIAA1199 gene is highly expressed in the inner ear, and a plurality of cases of mutation in the KIAA1199 gene involving amino acid substitution were found in family lineages having nonsyndromic hearing impairment (see, for example, Non-Patent Documents 1 and 2). Also, in a variety of cancer cells and cancer tissues such as cultured breast cancer cells and stomach cancer, the KIAA1199 gene is highly expressed (see Non-Patent Documents 3 and 4). The KIAA1199 gene is highly expressed in colorectal cancer, and the level is reduced through administration of an anti-cancer agent (see Non-Patent Document 5). On the basis of the aforementioned findings and use of the KIAA1199 gene for cancer genetic diagnosis and drug development, some patent applications were filed (Patent Documents 5 to 9).
Meanwhile, some analyses by means of a microarray have revealed that the KIAA1199 gene may serve as a marker for deformans arthritis (Patent Document 10) and rheumatoid arthritis and osteoarthritis (Patent Document 11).
However, due to complex mechanisms in relation to cancer and inflammation, no specific physiological functions of the KIAA1199, including physiological activities and involvement in cancer and inflammation, have been clearly elucidated.